“So attention must be paid!” insists Willy Loman’s wife in Arthur Miller’s Death of a Salesman. “He’s not to be allowed to fall into his grave like an old dog.”

The other day someone sent me a link to an article in the Chronicle of Higher Education. If you’re someone who’s concerned about the future of academic science in the USA, some of what the author brings to light may furrow your brow, deeply.

Jacob E. Levin, assistant vice chancellor for research at the University of California at Irvine points to a federal report showing that “in the early to mid-1960s, the National Institutes of Health funded more than 50 percent of the proposals it received,” he writes.

“Throughout the 70s and 80s, grant-success rates remained healthy and reliable at 30 to 40 percent. Now they have dropped to around 15 percent (lower for some institutes), and the average age of independent investigators when they receive their first grant is creeping into the mid-40s.”

And there’s more:

“Significantly, funding-success rates for certain subpopulations, like mid-career scientists, have sunk even lower. The time it takes to review grants has increased, and more and more resources are being poured into larger collaborative efforts (such as the $2-billion Clinical and Translational Science Awards), leaving many investigators out in the cold, without sufficient support to continue their work for extended periods of time.”

Weighing in on the problem with a word of advice, is Dede Corvinus, director of the Office of Research at UNC-Chapel Hill School of Medicine:

“In addition to the difficulty of getting independent funding from the agency, junior faculty have to deal with promotion and tenure committees who expect the time line of accomplishments to be what it was in the past. Institutions need to rethink how to recognize young faculty for their contributions to successful team efforts.”

Rosemary Simpson, chief operating officer of the North Carolina Translational and Clinical Sciences Institute (NC TraCS), says she worries these days about junior faculty researchers, “…for if you don’t get your first R01 until you are in your mid-forties, then you have only about 20 more years to grow your career.

“It has taken me years to understand why some faculty never retire and keep working at the bench well into their 80s. It is because their working life is so much shorter than the rest of us.”

Willy Lowman struggled to leave his mark on the world. In various ways, so do we all, including our nation’s scientists.

Yes, attention must be paid. The NIH budget is under attack, as are the budgets for the National Science Foundation, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the Agency for Healthcare Research and Quality. So Act now.

By my lights, the image below is a kind of scientific marvel, a visual representation of a recent research success that has taken more than15 years to accomplish: isolation of a pure extract of the tumor suppressor protein BRCA2 from human cells.

The photo shows two side-by-side molecules of BRCA2 protein, appropriately shaded pink and bound to a circular DNA constructed to contain a binding site for the protein.

This visualization showing that the protein acts as a pair when bound to DNA was produced by Drs. Sarah Compton and Jack Griffith at the UNC Lineberger Comprehensive Cancer Center.

In a report published in Nature Structural & Molecular Biology, August 22, 2010, Stephen West of the London Research Institute, Cancer Research UK, and co-authors, including Compton and Griffith, describe the first purification of the BRCA2 protein which is produced by a gene whose loss greatly increases the occurrence of breast cancer.

The feat, achieved independently by three labs, were published online August 22 in the journals Nature and Nature Structural & Molecular Biology.

The findings could lead to a better understanding of how the protein works and how BRCA2 sequence mutations cause cancer. They may also open a door to the development of new cancer therapies that could block the disease causing process.

The protein has been notoriously difficult to isolate until now. As one of the largest proteins in a cell, it can’t be expressed in bacteria in order to be isolated like other proteins – it is three to four times too big, Stephen West told New Scientist magazine. As a result, researchers have until now been using fragments of the protein to understand its function.

As summarized in Nature, the three studies examined the interaction of the full-length BRCA2 protein with other proteins, primarily one called RAD51, which repairs DNA by assembling around breaks in the strands, and forming filaments through which nucleotides (components of DNA) are pulled in to fix the DNA gaps.

By studying the interaction between BRCA2 and RAD51, all three teams confirmed that BRCA2 helps RAD51 to initiate filament growth.

I’m not surprised that Jack Griffith was involved in this important research. The Kenan distinguished professor’s electron microscopy (EM) work includes a number of breakthroughs beginning in his grad school years.

For his Ph.D. work at Cal Tech, Griffith developed the EM technology needed to directly visualize bare DNA and DNA-protein complexes. His methods involved carefully controlled rotary shadow casting with tungsten and mounting the DNA on very thin carbon films.

Using the methods he developed, Griffith, with Jack Kornberg and Joel A. Huberman published a paper showing an EM image of Escherichia coli DNA polymerase I bound to DNA. This was not only the first EM image of DNA bound to a known protein, but it also showed that electron microscopy had the potential to provide quantitative information about macromolecular assemblies involving DNA.

And in 2002, Griffith and colleagues used quantitative techniques to map the DNA involved in Fragile X syndrome. It has been known that in people with Fragile X, a particular DNA sequence is repeated too often — as many as two thousand times, compared to only seventeen to thirty times in normal DNA. But it wasn’t known how that repetition, called expansion, contributed to Fragile X syndrome.

“We showed that in Fragile X, that expansion creates a segment of the chromosome that is very unorganized and unprotected relative to the rest of the chromosome,” Griffith told UNC’s Endeavors magazine. The work provides a clue to the molecular causes of the disorder.

Oh boy, here we go again. Yesterday’s banning of human embryonic stem cell research by a federal judge brings us back to the issue raised by this blog on March 12, 2009.

We were celebrating a heady moment: At last, a breath of fresh air for biomedical science, the removal of Bush administration federal financing restrictions on embryonic stem cell research.

But the so-called Dickey-Wicker Amendment loomed as a potential spoiler. And in the last few blog paragraphs I tried to read some tea leaves when taking a stab at seeking a hidden message to Congress in the Obama administration’s wording of the new law:

Does our new president expect Congress to alter the amendment? Is there enough unflappable support to do so? In the new law he signed a few days ago, one might find a hint:

‘Sec. 2. Research. The Secretary of Health and Human Services (Secretary), through the Director of NIH, may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent permitted by law. ‘

Hmmm. Could be a nice way of asking Congress to change the darn thing, for good….

This morning’s on-line edition of the Boston Globe summarizes the problem succintly:

It notes that “the Obama administration attempted to walk a scientific and moral tightrope in its regulations, which allow scientists to work only with stem cells derived from donated embryos. The donors must give their explicit permission for scientific use of the embryos, typically stored at in vitro fertilization clinics.

“Even then, federal dollars cannot be used in the process of harvesting the cells; federal funds are limited to studying the cells after they have been extracted.

[Judge] “Lamberth ruled, in essence, that is a distinction without merit under a 1996 law known as the Dickey-Wicker Amendment.

“‘Had Congress intended to limit the Dickey-Wicker to only those discrete acts that result in the destruction of an embryo, like the derivation of [embryonic stem cells], or to research on the embryo itself, Congress would have written the statute that way,'” the judge concluded. “‘Congress, however, has not written the statute that way, and this court is bound to apply the law as it is written.'”

Recent polls show that the majority of Americans are in favor of continuing human embryonic stem cell research. One wonders if sufficient public pressure and political support exists to change the amendment.

Yes, it really pains one to say that Hard Science has suffered a month in the doldrums. So it’s with some relief that we write to report that the enzyme known as PAP promises long-lasting pain relief, possibly for pain after surgery.

It was October 2008 when UNC neurophysiologist Mark Zylka reported in Neuron that prostatic acid phosphatase appeared to be eight times more effective at suppressing pain than morphine.

Now his latest work published in the Journal of Neuroscience shows that the enzyme could pack a big punch in the battle against chronic pain.

“If you inject PAP before nerve injury or before causing inflammation, PAP has very long-lasting effect on the pain sensitization that follows,” said senior study author Zylka, assistant professor of cell and molecular physiology and a member of the UNC Neuroscience Center. “It has the potential to block or dramatically reduce pain, possibly in surgical settings.”

What’s more, PAP appears to keep on blocking pain symptoms long after it is injected.

Tens of millions of Americans suffer from chronic pain. This long-lasting pain is caused by a series of events along nerve cell membranes that make neurons hypersensitive. Injecting excess PAP into the system triggers a parallel series of reactions that makes it harder for this pain cascade to fire.

“Essentially PAP robs the cell of PIP2 so pro-pain pathways can’t signal as effectively.” explained Zylka. The team conducted their research using cell cultures and mice.

Using PAP to deplete PIP2 represents a promising new approach to treating chronic pain. “This is something people haven’t really focused on yet,” Zylka said. “We’re going right to the source of these pathways.”

In previous studies using mice, the team found that injecting PAP after an injury reduces sensitivity to both heat (like touching a hot burner) and mechanical sensitization (like the pain from brushing sunburned skin) for three days.

This time, the researchers took it a step further by injecting PAP before the injury. The effects lasted for the duration of the study—up to nine days.

Patients undergoing major surgery occasionally receive pain relievers through spinal injections just before the surgery begins. This study suggests that injecting PAP along with those other pain relievers might reduce patients’ need for analgesics like opiates in the days following surgery. Future studies with patients will be needed to verify these possibilities.

“Ultimately, we’re very interested in other pain-related mechanisms that regulate PIP2 levels in cells. Any one of those mechanisms could be targeted for the treatment of chronic pain,” Zylka said.

Such research could provide new drugs for patients who already have chronic pain.

Within the body of a healthy Homo sap adult, microbial cells are estimated to outnumber human cells by a factor of ten to one. The total number of genes associated with the human microbiome could exceed the total number of human genes by a factor of 100 to one.

So abundant among us are these fellow travelers that each of us should qualify for MFTN: most- favored nation trading status. Or, at the very least, group health insurance.

These bacterial communities, complete with their own genomes, are still largely unstudied, leaving almost entirely unknown their influence upon human development, physiology, immunity, and nutrition.

In other words, it’s a good bet that we play host to a lot of good guys and bad guys.

Now a new UNC study suggests that a shift in the balance between the “good” bacteria and the “bad” bacteria that populate our gut could be a harbinger of colon cancer.

The findings, which appear online in the May/June issue of the journal Gut Microbes, could lead to strategies to identify people who are at high risk as well as ways to manipulate the microbiota to prevent colon cancer.

“We think something happens to tip the balance away from the beneficial bacteria and in favor of microbes that make toxic metabolites and are detrimental to our health,” said senior study author Temitope Keku, Ph.D., research associate professor of medicine at UNC.

“By pinpointing these bacterial culprits, we can not only identify people at risk, but also suggest that they include the good bacteria in their diet,” added Keku. “And what a great way to address colon cancer – you could know your risk and lower it by eating your yogurt every day.”

Researchers have known for decades that the bacteria harbored in our bodies are not innocent bystanders but rather active participants in health and disease. Yet only recently have molecular methods evolved to the point that they can identify and characterize all of our microbial residents.

Keku and her colleagues used these methods to determine the different bacteria groups contained within biopsies from 45 patients undergoing colonoscopies. They uncovered a higher bacterial diversity and richness in individuals found to have adenomas than in those without these colorectal cancer precursors. In particular, a group called Proteobacteria was in higher abundance in cases than in controls, which was interesting considering that is the category where E. coli and some other common pathogens reside.

It’s still not clear whether alterations in bacterial composition cause adenomas, or if adenomas cause this altered balance.

In order to tell if it is the chicken or the egg, Keku plans to conduct more mechanistic studies, such as testing whether certain groups of bacteria promote cancer growth in animal models. She is also expanding the study to analyze samples from 600 patients using next-generation sequencing technology.

The ultimate goal may be to determine if the differences found in the mucosa lining the colon also exist in the fecal matter that passes through the colon. If so, it could mean less invasive screening for cancer and even more cancers being caught earlier, when survival rates are higher.

“We have come a long way from the time when we didn’t know our risk factors and how they impact our chances of getting colon cancer,” said Keku. “But now that we can look at bacteria and their role, it opens up a whole new world and gives us a better understanding of the entire gamut of factors involved in cancer – diet, environment, genes, and microbes.”

Some of you might recall a time when a popular idea regarding mental illness was that the fault, dear reader, was not in our genes but in the way we communicated with each other.

In the mid-1950s, a number of social scientists and psychotherapists developed proposals that attributed schizophrenia to the exposure to, and participation in, dysfunctional communication patterns in the family.

Some of the concepts flying around like drunken pelicans included “double-bind communication,” “pseudomutuality, and “pseudohostility.” (For a nifty overview, circa 1997, see this article.)

It was an intriguing idea that sort of jelled with a lot of us Homo saps who viewed mental illness as w-a-a-a-y more environmentally than genetically determined. And even into the early 1960s, the majority of undergrad psych students would feel compelled to agree.

Today, in the nature versus nurture game, we tend to be interactionists in our view of schizophrenia. We know it to be a debilitating mental disorder affecting one in 100 people worldwide, that most cases aren’t detected until a person starts experiencing symptoms like delusions and hallucinations as a teenager or adult. And by that time, the disease has often progressed so far that it can be difficult to treat.

Infant’s brain image on left shows the larger lateral ventricles and a generally larger brain overall. Image provided by John Gilmore, MD.

Now new research published online in the American Journal of Psychiatry offers the first evidence that early neonatal brain development may be abnormal in males at genetic risk fo schizophrenia.

The scientists used ultrasound and MRI to examine brain development in 26 babies born to mothers with schizophrenia. (Having a first-degree relative with the disease raises a person’s risk of schizophrenia to one in 10.)

Among boys, the high-risk babies had larger brains and larger lateral ventricles—fluid-filled spaces in the brain—than babies of mothers with no psychiatric illness. The new findings were detectable in babies only a few weeks old.

“It allows us to start thinking about how we can identify kids at risk for schizophrenia very early and whether there things that we can do very early on to lessen the risk,” says lead study author John H. Gilmore, MD, professor of psychiatry and director of the UNC Schizophrenia Research Center.

“Could it be that enlargement is an early marker of a brain that’s going to be different?” Gilmore speculates.

No difference was found in brain size among girls in the study. This fits the overall pattern of schizophrenia, which is more common, and often more severe, in males.

The findings, o course, do not necessarily mean the boys with larger brains will develop schizophrenia. Relatives of people with schizophrenia sometimes have subtle brain abnormalities but exhibit few or no symptoms.

“This is just the very beginning,” said Gilmore. “We’re following these children through childhood.”

The team will continue to measure the children’s brains and will also track their language skills, motor skills and memory development. They will also continue to recruit women to the study to increase the sample size.

A large international consortium of researchers, including scientists at the University of North Carolina at Chapel Hill, have announced new discoveries that could help clarify the genetics of autism.

Their findings published online June 9th in Nature, support an emerging consensus among scientists that autism is caused by many “rare variants” or genetic changes found in less than one percent of the population.

While each of these variants may only account for a small fraction of autism cases, collectively they appear to account for a greater percentage of individuals within the autism community. They are also providing into possible mechanisms involved in the disease.

The Autism Genome Project (www.autismgenome.org) collected genotyping data from 1,000 individuals with autism spectrum disorder, or ASD, and 1,300 without ASD. They found that people with the disorder tend to carry submicroscopic insertions and deletions called copy number variants, or CNVs, in their genome. Some of these variants appear to be inherited, while others are considered new because they are found only in affected offspring and not their parents.

These CNV in individuals with ASD tend to disrupt genes previously reported to be associated with autism or intellectual disabilities.

The study also identified new genetic risk factors for autism (genes known scientifically as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus.)

Some of these genes belong to nerve synapse-related pathways, while others are involved in cell proliferation, cellular movement, and intracellular signaling – functional targets that may lead to the development of new treatment approaches.

“These findings provide further evidence that autistic behavior is the result of many rare, small genetic changes,” said Joseph Piven, MD, study co-author and a lead AGP consortium investigator. Piven is also Sarah Graham Kenan Professor of Psychiatry at UNC and director of the Carolina Institute for Developmental Disabilities.

“While genetic abnormality or relevant CNV identified appears to account for only a handful of affected individuals, taken together these various CNVs in different locations throughout the genome are beginning to account for a significant number of occurrences of autism in the population. Identifying the genes and biological pathways associated with these genes will eventually lead us to new treatments for autism based an understanding of the underlying biological causes.”

Geraldine Dawson, PhD, research professor of psychiatry at UNC, also coauthored the new study.

The AGP consists of 120 scientists from more than 60 institutions representing 11 countries who formed this first-of-its-kind autism genetics consortium. Since 2002, group members have shared their samples, data, and expertise to facilitate the identification of autism susceptibility genes.